含苯磺酰胺结构单元的新型苯乙酸衍生物的合成及其PPAR激动活性

Synthesis and PPAR activities of novel phenylacetic acid derivatives containing sulfonamide moiety

以对氨基苯乙酸为起始原料,采用氨基磺酰化、羧基酯化、酰胺脱脂肪酰基及氨基酰基化等方法,经多条路线合成得到6个中间体和20个含有苯磺酰胺和对氨基苯乙酸结构单元的目标分子,24个新分子的结构经1H NMR、13C NMR和HR-MS证实。体外过氧化物酶体增殖物激活受体(PPAR)激动活性初步筛选结果显示,多数分子的PPAR相对激动活性不强,但有4个化合物的PPAR相对激动活性超过58%,其中TM2-i达到81.79%。由此首次发现,含有苯磺酰胺和对氨基苯乙酸结构单元的某些化合物具有潜在抗糖尿病活性。本研究还发现,SOCl2/醇体系可一步实现烷基羧酸的酯化和N-苯基脂肪酰胺脱酰基化,为某些酯基和酰胺基共存分子的选择性反应提供了新方法。

The discovery of high performance leading antidiabetic compounds containing sulfonamide and 4-aminophenylacetic acid moieties is reported. This was achieved by the synthesis of 6 intermediates and subsequently 20 target molecules using 4-aminophenylacetic acid as the starting materials, and through a few synthetic routes aided by multi-step reactions including sulfonylation of amino group, deacylation of amides and esterification of carboxyl group, as well as acylation of amino group. The chemical structures of the twenty-four new compounds were determined using 1H NMR, 13C NMR and HR-MS techniques. Screening in vitro of their peroxisome proliferator-activated receptor （PPAR） activation activities showed weak relative PPAR activation activities to most of the target molecules. However, 4 target molecules exhibit PPAR over 58%, and as high as 81.79% for TM2-i, presenting itself as potent leading compound for antidiabetic drugs. This research also confirms that it is probable to achieve esterification of carboxyl group and deacylation of fatty acid N-phenyl amides concurrently in SOC12/alcohol solvent system. This provides new synthetic method for the selective reaction within molecules containing both carboxyl and N-aryl amido groups of fatty acids.